Abstract: Fever is common in postoperative neurosurgical patients.
When fever is present, thermoregulatory responses regulate body
temperature within a range that appears to have an upper limit.
Endogenous substances, such as arginine vasopressin (AVP), modulate the
thermoregulatory response during fever and are referred to as endogenous
antipyretics. Endogenous antipyretics attenuate fever by influencing the
thermoregulatoty neurons in the preoptic region and anterior
hypothalamus and in adjacent septal areas. Well known for its
antidiuretic and vasopressive properties, AVP plays an important role in
antipyresis via the ventral septal area of the limbic system. Evidence
suggests that there may be a synergistic relationship between AVP
receptors and cyclo-oxygenase enzyme during antipyresis, and the
presence of AVP may enhance the efficacy of nonsteroidal antipyretic drugs. On &e other hand, there is evidence that increased levels of
AVP released during fever may play a role in febrile seizures. Although
the antipyretic effect of AVP release during fever is beneficial,
excessively high levels of A VP may be detrimental.

**********

Fever is the most common symptom of disease and, unlike
hyperthermia, is a regulated elevation of body temperature that appears
to have an upper limit. During fever, there is an upward displacement of
the hypothalamic set point mediated by pyrogenic cytokines (Kluger,
1991; Saper & Breder, 1994). Hyperthermia, on the other hand, is an
increase in body temperature without a change in the hypothalamic set
point (Dinarello, Cannon, & Wolf, 1988).

More than 50 years ago, DuBois (1949) reported that fever rarely
exceeds 41.1[degrees]C. However, his observations were made prior to the
wide use of antibiotics and modem-day medical technology. Practitioners
know today that thermoregulatory neurons in the preoptic region and
anterior hypothalamus (POAH) and in adjacent septal areas are influenced
by endogenous pyrogens to produce fever and secrete antipyretic factors
to attenuate fever (Boulant, 1997; Mackowiak & Boulant, 1996).
Therefore, body temperature in fever appears to have an upper limit due
to influences of endogenous antipyretic substances such as the
following:

* arginine vasopressin (AVP)

* alpha-melanocyte-stimulating hormone (([alpha]-MSH)

* glucocorticoids

* corticotropin-releasing factor (CRF)

* adrenocorticotropic hormone (ACTH)

* lipocortin

* thyrotropin-releasing hormone (TRH)

* gastric inhibitory peptide

* neuropeptide [gamma]

* bombesin

* tumor necrosis factor (TNF)

* uromodulin (Kluger, 1991).

At least three pituitary hormones appear to function as endogenous
antipyretics: AVP, ([alpha]-MSH, and ACTH. Among the endogenous
antipyretic factors, AVP, which modulates fever by lowering the
hypothalamic core temperature set point (Pittman, Malkinson, Kasting,
& Veale, 1988), has been studied most extensively.

AVP has long been known for its participation in control of
arterial blood pressure (Oliver & Shafer, 1895) and water excretion
by the kidneys (Farini, 1913; Von den Velden, 1913). Even though there
is early evidence of AVP's antipyretic activity (Cushing, 1932),
most research on this topic has occurred within the last 20 years. This
article reviews the pharmacodynamics of AVP and addresses the role of
AVP during fever, including its role during dehydration and fever, its
interaction with antipyretic drugs, and its neuromodulator role during
febrile convulsions.

Pharmacodynamics

Vasopressin, also known as antidiuretic hormone, is produced in the
supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the
hypothalamus and stored in the posterior pituitary, ha the rat,
vasopressinergic cells also have been identified in the lateral
ventricle, stria terminalis, stria medullaris, septum, hippocampus,
amygdala, medulla oblongata, and spinal cord (Buijs, 1978; Buijs, Swaab,
Dogterom, & Van Leeuwen, 1978). AVP is a nonapeptide with a 6-amino
acid ring and a 3-amino acid side chain. In humans and most other
mammals, arginine is found in position 8; in pigs and related species,
lysine is found in position 8 (Klonoff & Karam, 1995).

Two types of AVP receptors have been identified. Vasoconstriction is mediated by V1 receptors on smooth muscle cells (Holmquist, Ludin,
Larsson, Hedlund, & Andersson, 1991). In addition, V1 receptors also
have been localized on principal cells of the cortical collecting duct
(Ando & Asano, 1993) but are absent from cells of papillary collecting ducts of the kidney (Portilla, Shyman, & Morrison, 1987).
V1-like receptors have been reported in brain regions such as the
ventral septal area (VSA), lateral septum, bed nucleus of the stria
terminalis, hippocampus in a number of animal species (Poulin, Lederis,
& Pittman, 1988; Szot, Ferris, & Dorsa, 1990), rostral end of
third ventricle, chorus, and area postrema (Gerstberger &
Fahrenholz, 1989).

Antidiuresis is mediated by V2 receptors detectable on the
basolateral membrane of principal cells in the collecting ducts (Kirk,
1988; Leite & Suki, 1990), luminal membrane cells of terminal inner
medullary collecting ducts (Nonguchi et al., 1995), and smooth muscle
cells in the renal pelvis (Kimoto & Constantinou, 1990). It has been
suggested that V2 receptors, not V1 receptors, are localized near the
anterio-ventral third ventricle and the paraventriculal, supraoptic,
suprachiasmatic nuclei, and neurohypophysis of the hypothalamus (Cheng
& North, 1989; Gerstberger & Fahrenholz, 1989). However, the
antipyretic effect of AVP is mediated by the V1 receptors in the fibers
and terminals of the VSA (Kasting, 1989).

Secretion and Control of Vasopressin

Two afferent pathways, one from baroreceptors and one from
osmoreceptors, control the secretion of AVP in the presence of
hypovolemia or hyperosmolality. Decreased extracellular volume causes
the baroreceptors to decrease their firing rate, signaling the
hypothalamus to increase secretion of AVP. When body water is lost,
osmoreceptors in the hypothalamus sense an increased body fluid
osmolarity and stimulate the secretion of AVP. During fever, AVP reduces
fever through a receptor-mediated action (Pittman, Naylor, et al.,
1988). Evidence now exists that AVP acts as a neurotransmitter in the
brain to exert antipyretic action during fever (Cooper, Kasting, Lederis
& Veale, 1979; Kasting, Veale, Cooper, & Lederis, 1981; Naylor,
Ruwe, Kohut, & Veale, 1985; Wilkinson & Kasting, 1987).

Thermoregulation During Fever

Fever is a complex adaptive host response initiated by autonomic,
neuroendocrine, and behavioral mechanisms as part of the acute phase
response to infection (Cooper, 1995). Fever occurs in response to a
challenge with endotoxins via the release of endogenous pyrogens by
systemic mononuclear phagocytes (Blatteis & Sehic, 2000). Endogenous
pyrogens (cytokines such as interleukin [IL]-1, tumor necrosis factor,
and IL-6) stimulate an upward resetting of the hypothalamic set point
(Cooper; Saper; 1998). Body temperature is sensed below the set point,
triggering heat-producing and heat-conserving mechanisms. When heal
production is greater than heat loss, heat is retained mad the core
temperature is raised (Kluger, 1991). The body responds to the higher
core temperature by initiating sweating and vasodilation during the
defervescent phase of fever (Cooper). Increased sweating decreases
plasma volume, which attenuates skin blood flow and sweating, causing a
further increase in core temperature (Doris & Baker, 1981).

A new hypothesis has been espoused about the initial rapid febrile
response to an endotoxin involving the vagus nerve. Before the
peripheral cytokines reach the POAH, a febrile response is elicited.
There is evidence to suggest that activation of subdiaphragmatic vagal afferent nerves may be an alternative neuronal communicator between
peripheral cytokines and the hypothalamus (Blatteis & Sehic, 1997).
In support, subdiaphragmatic vagotomy blocks the induction of IL-1-beta
gene expression in the brain (Hansen, O'Connor, Goehler, Watkins,
& Maier, 2001; Laye et al., 1995). in other words, the initial onset
of the febrile response may be due to a neuronal rather than humoral
pathway. During this acute phase, whether activated by neuronal or
humoral activity, body temperature is rising to approximate the new set
point, and a hypothermic state is present. As a result, heat-generating
and heat-conserving mechanisms are initiated.

Antipyretic Properties of AVP

Experimental evidence indicates the antipyretic action of AVP
exists in specific central sites. For example, AVP perfused into the VSA
of the sheep, rat, and rabbit suppresses endotoxin fever (Cooper et al.,
1979; Kasting et al., 1981; Naylor et al., 1985; Wilkinson &
Kasting, 1987), whereas AVP injected into the third cerebral ventricle
and the lateral septum in rabbits (Bernardini, Lipton, & Clark,
1983), the lateral cerebral ventricle in macaque monkeys (Lee, Mora,
& Myers, 1985), and the fundus striati in rats (Kremarik,
Freund-Mercier & Pittman, 1995) increases or has negligible effects
on core temperature response to lipopolysaccharide (LPS) injection.
Therefore, the VSA of the limbic system is believed to be the site where
the antipyretic effects of AVP are mediated. These findings reinforce
the differences in actions of AVP with different methods of application.
Because of species-specific anatomical and physiological differences in
thermoregulation, attention also needs to be paid to the animal model
used if inference to other species, especially humans, is to be made.

Support for the antipyretic properties of AVP has been documented
by an enhanced febrile response following AVP blockade. V1 antagonists
injected into the VSA of febrile rats enhanced file febrile response;
however, V2 antagonists had no effect (Cooper, Naylor, & Veale,
1987). When live bacteria were injected into rats, fever was enhanced
following administration of V1 antagonists (Cridland & Kasting,
1992). These results suggest that endogenous AVP functions as a
neuromodulator in natural fever as well as in endotoxin-induced fever.

In rats infused with IL-1 into the lateral cerebral ventricle to
induce fever, pretreatment with an AVP V1 antagonist into the VSA
enhanced the magnitude and duration of the febrile response (Cooper et
al., 1987). Similar results were reported when rats received chronic
infusion of V1 antagonist prior to injection of live bacteria (Cridland
& Kasting, 1992). Back, Roth, Kluger, and Zeisberger (1994)
investigated the effects of V1 receptor antagonist on the febrile
response to intramuscular injection of LPS 20 [micro]g/kg and reported
that electrical stimulation of the PVN of guinea pigs attenuated the
febrile response. However, this response was partly reversed by a
simultaneous intraseptal microinfusion of a V1 receptor antagonist.
Taken together, these results support a role for AVP in antipyresis with
natural and induced fevers.

Disparate results concerning the antipyretic abilities of AVP have
been reported in Brattleboro rats that are deficient in AVP. Following
administration of endotoxin, endogenous pyrogens, or prostaglandin, the
febrile response in Brattleboro rats was not enhanced (Eagan, Kasting,
Veale, & Cooper, 1982; Ruwe, Veale, & Cooper, 1988). In
contrast, male rats with reduced secretion of AVP produced by long-term
castration had enhanced febrile responses (Pittman, Malkinson, et al.,
1988). These results do not rule out the role of AVP during antipyresis
but rather suggest that several endogenous antipyretics may be involved
in the febrile response (Moltz, 1993).

AVP concentration in the plasma and limbic septum increased during
osmotic stimulation in rats (Demotes-Mainard, Chaveau, Rodriguez,
Vincent, & Poulain, 1986; Landgraf, Neuman, & Schwarzberg,
1988). There is evidence that hypovolemia and hyperosmolality, both
strong stimuli of AVP, are antipyretic (Kasting, 1986; Kasting et al.,
1981). In ewes injected intravenously with S. abortus LPS, Kasting et
al. showed that loss of blood volume through hemorrhage (i.e., 20% of
estimated blood volume) attenuates fever in sheep. In a similar study
(Kasting, 1986), hemorrhage of 20% blood volume in rats also reduced the
febrile response to E. call LPS. In addition, infusion of hypertonic saline, another potent stimulus of AVP, also attenuated LPS-induced
fever. These findings suggest that AVP is centrally released during
osmotic stimuli and hypovolemia and that 24-hour water deprivation,
resulting in a combination of hypovolemia and hyperosmolality, would
also be expected to release central AVP and, therefore, induce
antipyresis.

Acetaminophen has replaced aspirin as the most commonly used
antipyretic (Maison et al., 1998; Prescott, 2000). However, recent
evidence supports the antipyretic efficacy of nonsteroidal
antiinflammatory drugs (NSAIDs). There is evidence that the NSAID indomethacin reduces fever more quickly and that its effects last longer
than those of acetaminophen and ibuprofen, another NSAID (Autret et al.,
1994; Purssell, 2002). Indomethacin, as an antipyretic, is 35 times more
potent than aspirin (Van Arman, Armstrong, & Kim, 1991).
Nonsteroidal antipyretic drugs inhibit prostaglandin synthesis by
decreasing cyclo-oxygenase (Dascombe, 1985). However, it has been
hypothesized that other antipyretic mechanisms exist, such as an
interaction with AVP (Wilkinson & Kasting, 1990, 1993).

During endotoxin fever, AVP-V1 antagonists infused within the
ventral septum block salicylate antipyresis but had no effect on the
antipyretic action of acetaminophen (Wilkinson & Kasting, 1990). AVP
levels in the VSA of conscious rats increased following antipyresis of
endotoxin-induced fever with indomethacin but not with acetaminophen
(Wilkinson & Kasting, 1993). This information would suggest that
salicylate and indomethacin-induced antipyresis are mediated by the
neuromodulatory function of endogenous AVP from within the VSA.

Febrile Seizures and Vasopressin

Little is known about the mechanism responsible for chidhood
febrile seizures. However, support for AVP as a neuromodulator in
febrile seizures is present in animal studies. Motor disturbances and
seizures were observed following intracerebroventricular (ICV)
administration of AVP in rats (Kasting, Veale, & Cooper, 1980). The
mean AVP level for rats after hyperthermia-induced seizures was
significantly higher than control levels (Burnard Pittman, Veale, &
Lederis, 1982). Rats with IL-1 alpha induced fever elicited a heightened
motor response following ICV injection of AVP (Poulin & Pittman,
1993 AVP infused in the VSA, the site of antipyretic action of AVP, also
initiates seizure activity in rats, which was enhanced with each
exposure (Pittman, Naylor, et al., 1988).

Similar findings in sheep were reported. AVP per fused into the
brain of sheep caused antipyresis, and following subsequent perfusions,
AVP levels wet increased and seizure activity was observed (Veal,
Cooper, & Ruwe, 1984). However, when AVP was diffused in the VSA of
Brattleboro rats, seizure activity was attenuated (Pittman, Naylor, et
al., 1988). Although antipyretic properties of AVP are mediated by V1
receptors, there is evidence that the effects of AVP on febrile seizure
activity are medicated by V2 receptors (Gulec & Novan, 2002).
Collectively, these results suggest that AVP released during fever
causes antipyresis; however, when disproportionately high, AVP may
promote seizure activity. To clarify the mechanism, further research on
fever-induced seizures is needed.

Gaps and Unexplored Areas in the Literature

Evidence supports a role for endogenous AVP in thermoregulation
during fever. Changes in the concentration of AVP have been demonstrated
during fever, dehydration, febrile convulsions, and administration of
antipyretic drugs. However, gaps in the literature related to AVP and
fever still exist. Research clarifying the antipyretic mechanisms of
vasopressin during dehydration is need ed. Dehydration is a frequent
cause of morbidity in vulnerable populations such as children, the
elderly, and immunocompromised persons. An understanding of the
mechanism of body temperature regulation during dehydration and fever is
needed to reduce morbidity, and even mortally, in high-risk populations.
Also, further research is needed to determine whether an increase in AVP
during dehydration affects the production of endogenous pyrogens.

During fever, vasopressin enhances the efficacy of the antipyretic
properties of indomethacin and salicylate. Although indomethacin is not
routinely prescribed for fever reduction in the clinical setting,
ibuprofen is often prescribed. The safety and efficacy of NSAIDs in
dehydrated patients, especially children and the elderly, need to be
explored. Whether NSAIDs are safe and effective antipyretics, especially
during dehydration, is crucial information for the healthcare
practitioner. Finally, the role of AVP as a neurotransmitter in febrile
seizures needs to be explored further. Based on the evidence that NSAIDs
may increase the level of AVP and that enhanced levels of AVP may
contribute to febrile seizures, the safety and efficacy of NSAIDs in the
presence of febrile seizures need to be investigated.

Implications for Practice

Patients who have undergone neurosurgical procedures are at risk
for developing a fever. It is important to evaluate each neurosurgical
patient's temperature elevation postoperatively because an elevated
temperature does not necessarily mean the presence of fever or an
infection. Cytokines that are released during surgery-induced
inflammation (Lin, Calvano, & Lowry, 2000) at, the same cytokines
released after a febrile stimulus. In addition, the same causes of
postoperative fever in general surgery patients (i.e., hypoventilation,
dehydration infection, stress, pulmonary congestion, atelectasis) are
present in the neurosurgical patient (Barker, 2002). Because of the
nature of neurosurgery, additional stressors are present (e.g., invasive
lines, catheters) that may contribute to the induction of postoperative
fever or infection (Barker).

Research results suggest that dehydration enhance the febrile
response. The daily fluid requirement during fever increases by 15% for
each 1[degrees]C elevation in body. temperature (Brensilver &
Goldberger, 1996). During defervescence, thermoregulatory responses to
elevated body temperature such as cutaneous vasodilation to transfer
heat from the core to the periphery and evaporative heat loss via
sweating or panting (Boulant, 1997) induce body water losses, inducing
dehydration (Morimoto & Itoh, 1998). Therefore, in the immediate
post-operative period, temperature monitoring, along with the detection
and prevention of dehydration, is crucial to the recovery of the
neurosurgical patient.

Summary

Neurosurgical nurses frequently encounter patient with fever as a
result of the sequelae of surgery. Fever unlike hyperthermia, is a
regulated elevation of body temperature and is a part of the acute phase
response to infection. Endogenous antipyretics, such as AVP, modulate
the thermoregulatory response during fever. AVP, which is produced in
the SON and PVN and stored in the posterior pituitary, reduces fever
through a receptor-medicated action. Results of animal research studies
suggest the the antipyretic action of AVP exists within the VSA of the
limbic system. Although osmotic stimuli such as hypovolemia and
hyperosmolality stimulate the release of AVP, the effects of dehydration
on fever are unclear.

Evidence suggests that there may be a synergistic relationship
between AVP receptors and cyclo-oxygenase enzyme during antipyresis, and
the presence of AVP may enhance the efficacy of nonsteroidal antipyretic
drugs. Although the antipyretic effect of AVP release is beneficial,
excessively high levels of AVP may enhance seizure activity during
fever. In view of the discovery that AVP levels are increased during
antipyresis with indomethacin and not acetaminophen, it is possible that
the use of acetaminophen may be more beneficial in febrile seizures than
NSAIDs.

Acknowledgments

I would like to acknowledge Vernon Bishop, PhD, Barbara J.
Holtzclaw, PhD RN FAAN, and Duane Proppe, PhD, of the University of
Texas Health Science Center at San Antonio for their early editorial
comments.

Kasting, N. (1989). Criteria for establishing a physiological role
for brain peptides. A case in point: The role of vasopressin in
thermoregulation during fever and antipyresis. Brain Research Review,
14, 143-153.